The long-term objective of our research is to develop microdevices for high-throughput measurement of quantal exocytosis from neurons and neuroendocrine cells. Patch-clamp electrophysiological and carbon-fiber electrochemical approaches represent the state-of-the-art for high time resolution and high information content assays of exocytosis but are slow and labor-intensive. Biochemical assays of secretion from cell populations have limited time resolution and can not resolve individual quantal fusion events. We will use microchip technology to develop devices that can assay quantal exocytosis from thousands of cells in a day in order to greatly accelerate the pace of basic neuroscience research. This approach will also enable, for the first time, rapid and high information content screening of drug candidates that affect exocytosis of neurotransmitter. For example, L-DOPA used to treat Parkinson's disease acts by increasing the quantal content of dopamine release. The approach will be interdisciplinary and will bring together investigators with expertise is biomedical, electrical and mechanical engineering, materials science, physics, electrochemistry, physiology and biophysics. The specific aims are: 1) Develop approaches to automatically target individual cells to electrochemical microelectrodes on microfabricated devices. 2) Develop approaches to stimulate exocytosis from cells on microdevices including rapid microfluidic solution exchange, photolysis of caged Ca and electrical stimulation of action potentials. 3) Integrate new electrochemical electrode materials into microdevices to increase sensitivity and performance. 4) Develop electronic instrumentation to allow simultaneous recording of many channels of electrochemical or electrophysiological data. The five-year goal of the project is to have actual devices on the market to serve the exocytosis research community that are at least an order of magnitude faster than current carbon-fiber approaches. Our first-year milestones for each aim are: 1) Position one or more cells at predetermined sites on a microchip. 2) Exchange extracellular solution in <100 ms on a microchip. 3) Characterize the electrochemical properties of a diamond-like carbon microelectrode. 4) Develop inexpensive modular circuitry for basic electrochemical measurements using off-the-shelf components that can be easily scaled for approximately 12 simultaneous channels.